Abstract Malaria remains a great public health challenge and is one of the most deadly human parasitic infections. Despite this, the human immune response to Plasmodium infection is not well understood. Further, the contribution of host versus parasite factors to disease pathogenesis is controversial. These major gaps in knowledge have thwarted efforts to develop vaccines and strategies that modulate the human immune response to malaria infection and prevent serious sequelae. While clinical studies during natural infection can provide insight into host responses, experimental models such as the Plasmodium yoelii (Py), P. berghei (Pb) or P. chabaudi (Pc) rodent models are truly instrumental to define underlying mechanisms. For instance, both in these models and in humans, key cytokines such as interferons (IFNs) play essential roles. Recent studies and our preliminary data report a type I IFN signature response during Plasmodium falciparum (Pf) infection in infected children and adults who manifest mild and severe disease. Both in the Pb experimental cerebral malaria (CM) and the Py YM (17X) mouse models, lack of type I IFN production or signaling protects mice from lethal infection, establishing that type I IFN is a key contributor to severe disease outcomes. Thus, in humans as well as in rodent models, type I IFN plays a significant role in the pathogenesis of malaria infections. Production of type I IFN is initiated upon recognition of pathogen-derived nucleic acid motifs by innate immune sensors including Toll-like receptors (TLR7, TLR9), RNA helicases (Mda5/MAVS), and the stimulator of interferon genes (STING). While Mda5 can mediate type I IFN production in all cell types, the TLR- and the STING- pathways are activated in antigen-presenting cells (APCs). Plasmodium-derived nucleic acids, specifically RNA, CpG and AT-rich DNA stem-loop motifs are sensed via all of the major pathways above, which support the idea that Plasmodium parasites do induce potent type I IFN responses. However, which cell types produce bioactive type I IFN during blood stage malaria in vivo, through which molecular sensing mechanisms, and in which tissues is virtually unknown. Given that type I IFN signatures are heavily noted in humans and its impact in various surrogate mouse models of blood stage malaria, these questions are highly relevant to understanding the pathogenesis of this stage of the infection, and potential therapies. The goal of this project is to explore these mechanisms and how this relates to severity of malaria.